This application addresses broad Challenge Area (15) Translational Science, 15-MH-109: Prefrontal cortex regulation of higher brain function and complex behaviors, which is directed to examine mechanisms by which the developing and mature prefrontal cortex interacts with other cortical and subcortical systems in the regulation of higher brain functions and complex behaviors. Understanding the cortical mechanisms mediating emotional regulation - both aversive and appetitive - is of critical importance for a variety of psychiatric disorders, such as Posttraumatic Stress Disorder (PTSD) and Drug Abuse. It is well established that Pavlovian conditioning is a powerful model to study the neural mechanisms involved in fear and appetitive learning. Additionally, when conditioned animals are repeatedly exposed to conditioned stimuli in the absence of unconditioned stimuli, the conditioned responses gradually decline. This reduction is referred to as extinction and results from a new form of inhibitory learning, rather than an erasure of the original memory. Considerable evidence suggests the medial prefrontal cortex (mPFC) is a major modulator of fear and appetitive conditioning and extinction by directly influencing the amygdala. However, neural mechanisms and interactions between the mPFC and the amygdala in the control of conditioned learning and extinction are still unclear. One potential molecular candidate underlying these effects may be brain derived neurotrophic factor (BDNF), a neurotrophin that is well known to be involved in neuronal plasticity and has been shown to be involved in learning, including fear and appetitive conditioning and extinction. BDNF is highly expressed in the medial prefrontal cortex and its tyrosine kinase receptor B (TrkB) is required for amygdala-dependent conditioning. Therefore, BDNF in the medial prefrontal cortex acting on TrkB receptors in the amygdala is a prime candidate for mediating the learning and/or extinction of fearful or appetitive memories. Using a variety of genetic and viral vector site-specific manipulations and sophisticated behavioral paradigms, this study will directly examine the hypothesis that BDNF-dependent plasticity in the prefrontal cortex is a critical modulator of the expression and extinction of previously conditioned fear or reward. More specifically, BDNF-dependent plasticity in the prelimbic cortex is required to modulate the expression of learned appetitive or fearful memories by targeting the basal nucleus of the amygdala, whereas BDNF-dependent plasticity in the infralimbic cortex is required to modulate extinction by targeting the lateral amygdale and/or the intercalated neurons of the amygdala. PUBLIC HEALTH RELEVANCE: Understanding the cellular mechanisms mediating emotional regulation - both aversive and appetitive - is of critical importance for a variety of psychiatric disorders, such as Posttraumatic Stress Disorder (PTSD) and Drug Abuse. Through a combination of anatomical, behavioral, molecular, and genetic techniques, these experiments have the potential to resolve an outstanding issue in the role of Brain Derived Neurotrophic Factor - a peptide known to be involved in emotional regulation- within the Prefrontal Cortex in modulating expression of appetitive and aversive memories, and extinction of those memories.